High throughput screening of a large and diverse collection of commercially available synthetic organic compounds (excluding peptides and oligonucleotides) has furnished us with several potent and selective classes of inhibitors of the immortalizing enzyme telomerase. In anticipation of a major expansion of our efforts to discover new chemical entities with anti-tumor properties, additional funding Is being sought. The award of this grant will be applied towards personnel support and new instrumentation. These resources will accelerate the drug discovery process In several important ways. First, we envision the selection and construction of random and focused chemical combinatorial libraries. In addition, more traditional medicinal chemistry techniques will supplement the generation of chemical diversity that arises from the rapid synthesis of analogs. This combined approach will optimize the process of lead generation. The results of this research program are expected to expand our understanding of structure activity relationships required for telomerase inhibition. Candidates with the highest potency and selectivity will be evaluated for in vivo efficacy through the integrated efforts of collaborators at Geron and the Memorial Sloan Kettering Cancer Center. During the final phases of this grant, our most critical objective will be to refine the structural requirements of lead compounds with respect to desirable drug properties, such as oral bioavailability and biological duration of action. Since relatively large quantities of a drug are required for thorough preclinical pharmacological evaluation, process chemistry will be developed to accommodate this demand.